Role of CD8IL-13 T cells in Chlamydia infection-associated immunopathology

描述（由申请方提供）：尽管采取了公共卫生措施和有效的抗生素治疗，但在美国和欧洲，沙眼衣原体生殖道感染在青少年/年轻人中的患病率为2-15%。人们普遍认为，有必要接种疫苗以减少其流行。早期的沙眼衣原体（眼部感染）疫苗提供的保护作用较差，并加剧了免疫病理学。开发安全的衣原体疫苗的关键是更好地了解免疫病理学。目前还没有衣原体免疫病理学的实用生物标志物。在C.其他人已经清楚地表明衣原体特异性CD 8 T细胞是免疫病理学和不育的重要介质。我们最近的研究表明，来自小鼠的衣原体特异性CD 8 T细胞克隆的一个亚群可以自我清除衣原体。鼠生殖道感染产生致瘢痕细胞因子IL-10、TNF和IL-13。这些CD 8克隆不受MHC Ia类分子的限制。类似的非Ia类限制性CD 8 T细胞克隆来源于患有C.沙眼生殖道感染。使用基因表达微阵列分析，我们已经确定了CD 8 IL-13 T细胞的分子指纹。基于现有的小鼠和人类衣原体文献，很明显，对衣原体生殖道感染的细胞免疫应答包括非Ia类限制性CD 8 T细胞。梭小鼠模型已经明确显示CD 8 T细胞是免疫病理学和不育的介质。我们推测，CD 8免疫病理学的机制是一个非MHC Ia类限制性CD 8 T亚群分泌IL-10，TNF β和IL-13。为了检验这一假设并研究潜在的免疫生物学，我们提出了以下具体目标：具体目标#1-利用过继转移研究CD 8 IL-13 T细胞在免疫病理学中的作用。我们有代表性的常规衣原体特异性CD 8 T细胞克隆，衣原体特异性CD 8 IL-13 T细胞克隆，和推定的细胞表面生物标志物，用于从免疫脾细胞或大量T细胞群中纯化CD 8 IL-13 T细胞。具体目标#2-研究衣原体特异性CD 8 IL-13 T细胞的活化途径和其他免疫生物学特性。利用现有的T细胞克隆和基因表达微阵列分析，我们将比较活化的常规CD 8与活化的CD 8IL-13 T细胞，以鉴定CD 8IL-13特异性免疫生物学;潜在地鉴定用于治疗干预的其他生物标志物和靶标。我们还将绘制衣原体特异性CD 8 T细胞克隆组的表位源蛋白。具体目标#3-对人体中的CD 8 IL-13 T细胞进行初步研究。使用小鼠模型中鉴定的CD 8 IL-13 T细胞亚群的推定生物标志物，我们将从健康个体的外周血中分离CD 8 T细胞，并确定人类中是否存在类似的CD 8 IL-13 T细胞亚群。

DESCRIPTION (provided by applicant): Chlamydia trachomatis genital tract infections have a prevalence of 2-15% in adolescents/young adults in the USA and Europe in spite of public health efforts and effective antibiotic therapy. It is widely accepted that a vaccine is necessary reduce its prevalence. An early C.trachomatis trachoma (eye infection) vaccine delivered poor protection and exacerbated immunopathology. Critical to developing a safe Chlamydia vaccine is a better understanding of immunopathology. Currently there are no practicable biomarkers for Chlamydia immunopathology. In the C. muridarum mouse model others have clearly shown that Chlamydia-specific CD8 T cells are important mediators of immunopathology and infertility. We have recently shown that a subset of Chlamydia-specific CD8 T cell clones derived from mice that self-cleared C. muridarum genital tract infections produce the scar-ogenic cytokines IL-10, TNF�nd IL-13. These CD8 clones are not restricted by MHC class Ia molecules. Similar non-class Ia restricted CD8 T cell clones have been derived from the peripheral blood of humans with C. trachomatis genital tract infections. Using gene expression microarray analysis we have identified a molecular fingerprint for CD8IL-13 T cells. Based on the existing mouse and human Chlamydia literature it clear that the cellular immune response to Chlamydia genital tract infections includes non-class Ia restricted CD8 T cells. The C. muridarum mouse model has unequivocally shown CD8 T cells to be mediators of immunopathology and infertility. We hypothesize that the mechanism underlying CD8 immunopathology is a non-MHC class Ia restricted CD8 T subset secreting IL-10, TNF�and IL-13. To test that hypothesis and investigate the underlying immunobiology we propose the following specific aims: Specific aim #1- to investigate the role of CD8IL-13 T cells in immunopathology utilizing adoptive transfer. We have representative conventional Chlamydia-specific CD8 T cell clones, Chlamydia-specific CD8IL-13 T cell clones, and putative cell surface biomarkers for purifying CD8IL-13 T cells from immune splenocytes or bulk T cell populations. Specific aim #2- to investigate the activation pathway and other immunobiology specific to Chlamydia-specific CD8IL-13 T cells. Utilizing existing T cell clones and gene expression microarray analysis we will compare activated conventional CD8 with activated CD8IL-13 T cells to identify CD8IL-13 specific immunobiology; potentially identifying additional biomarkers and targets for therapeutic intervention. We will als map the epitope source proteins for the Chlamydia-specific CD8 T cell clone panel. Specific aim #3- perform a preliminary investigation of CD8IL-13 T cells in humans. Using putative biomarkers for the CD8IL-13 T cell subset identified in the mouse model we will isolate CD8 T cells from the peripheral blood of healthy individuals and determine whether a similar CD8IL-13 T cell subset exists in humans.